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Thiol redox sensors in proteins are emerging as key therapeutic targets, as they govern fundamental signalling pathways and provide crucial sites for covalent drug development. A key mediator of their function is the presence of redox-active disulphides, which act as molecular switches due to their ability to induce reversible protein conformational changes. However, despite their importance in cellular regulation and therapeutic relevance, only a limited number of redox-active disulphides have been identified to date. To address this, we developed ReDisulphID, a structural bioinformatics platform that systematically identifies druggable redox-active disulphides. Using this platform, we discovered novel druggable redox sensors in MLYCD, TFIIB, and PEPD. Functional analysis of PEPD revealed that its redox sensor activates the tumour suppressor p53. Furthermore, we identified a compound that activates p53 through direct thiol modification of the sensor in PEPD, demonstrating how ReDisulphID can advance the discovery of protein redox sensors and support thiol-targeted drug development.
Coleman et al. (Fri,) studied this question.